Targeting Wnt/β-catenin signaling by TET1/FOXO4 inhibits metastatic spreading and self-renewal of cancer stem cells in gastric cancer

Qi, J.; Cui, D.; Wu, Q.N.; Zhao, Q.; Chen, Z.H.; Li, L.; Birchmeier, W.; Yu, Y.; Tao, R.

Targeting Wnt/β-catenin signaling by TET1/FOXO4 inhibits metastatic spreading and self-renewal of cancer stem cells in gastric cancer

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Item Type:	Article
Title:	Targeting Wnt/β-catenin signaling by TET1/FOXO4 inhibits metastatic spreading and self-renewal of cancer stem cells in gastric cancer
Creators Name:	Qi, J., Cui, D., Wu, Q.N., Zhao, Q., Chen, Z.H., Li, L., Birchmeier, W., Yu, Y. and Tao, R.
Abstract:	Metastasis is the main cause of death for patients suffering gastric cancer. Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critical attributes of metastasis, both of which are regulated tightly by DNA methylation and Wnt/β-catenin signaling. Here, we studied the functions of DNA dioxygenase TET1 in regulating Wnt signaling and in gastric cancer metastasis. Knocking-down and overexpressing TET1 in gastric cancer cells promoted and inhibited metastatic spreading to the liver in immune-deficient mice, respectively. TET1 showed inhibitory effects on metastasis-related features -EMT and CSC, which were reversed by interfering with Wnt/β-catenin signaling. RNA-sequencing identified FOXO4 as a direct transactivating target of TET1. FOXO4 directly interacted with β-catenin and recruited it in the cytoplasm, so as to inhibit β-catenin-mediated transcription of Wnt target genes, including CSC marker EpCAM. Moreover, modulation of FOXO4 could reverse the effects of TET1 manipulation on EMT and self-renewal of CSCs. The analysis with clinical samples confirmed the value of FOXO4 as an independent prognostic predictor of patients' overall survival. Taken together, regulation of Wnt signaling by TET1/FOXO4 is essential for metastasis-associated cellular properties, and targeting TET1/FOXO4/β-catenin pathway may serve as promising therapeutics in the prevention and treatment of gastric cancer metastasis.
Keywords:	Gastric Cancer, TET1, FOXO4, Wnt Signaling, Cancer Stem Cell, Metastasis, Animals, Mice
Source:	Cancers
ISSN:	2072-6694
Publisher:	MDPI
Volume:	14
Number:	13
Page Range:	3232
Date:	30 June 2022
Official Publication:	https://doi.org/10.3390/cancers14133232
PubMed:	View item in PubMed

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